Research in this program is focused on the basic mechanisms by which the host mobilizes and modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal models (bacterial induced rodent arthritis; knockout and transgenic mice) for in vivo analysis. In addition, human conditions of chronic inflammatory disease in response to foreign implants, infectious pathogens, or of unknown etiology are explored at the cellular, molecular and biochemical levels. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion and the switch to pathogenesis underlies the development of strategies for modulating chronic pathogenic inflammatory diseases. In an experimental model of arthritis, we have characterized the immunopathology through phenotypic, functional and morphologic parameters, in addition to DNA microarrays and ribonuclease protection assays, to identify targets for therapeutic intervention including leukocyte adhesion, signal transduction, cytokines, proteases, and nitric oxide. Gene transfer of a TNF antagonist locally within the joint suppressed synovitis and tissue destruction. New insights into the regulation of immune function through CD4+CD25+ regulatory T cells which express TGF-beta on their surface raise the prospect of novel approaches to controlling immunological tolerance. This key population of suppressor T cells is important in prevention and inhibition of autoimmune diseases, allotransplant rejection and in cancer pathogenesis. Another endogenous immunoregulatory molecule, SLPI, was found to be instrumental in host defense to an intracellular parasite. Delineation of the immune response to L. major in SLPI deficent mice will help define the role of SLPI in innate and adaptive immunity and its potential as a therapeutic agent in the treatment of infectious and inflammatory diseases.